The results of this study demonstrate that FCMR plays a role in B cell differentiation, function and homeostasis. Mice deficient in FCMR exhibit multiple alterations in early B cell development, the distribution of mature B cell subsets, responses to antigenic challenge and are predisposed to autoimmunity. The fact that many of these changes mirror those observed in mice lacking sIgM indicates that FCMR is a critical sensor of circulating IgM and provides a basis for understanding a number of its functions in health and disease. The impaired B cell development in Fcmr deficient mice occurred as early as at the pre-B cell stage. The generation of pre-B cells is driven by pre-BCR-mediated clonal proliferation for 6 divisions followed by cell cycle arrest and the differentiation of small pre-B cells. Deficiencies in pre-BCR signaling caused by poor expression of the pre-BCR at the cell surface or disrupted signaling machinery downstream of the pre-BCR cause severe defects in pre-B and subsequent immature B cell development. While the numbers of pro-B cells in Fcmr deficient mice were moderately reduced, the subsequent development of large pre-B cells was not significantly affected, indicating that the pre-BCR functions normally in these cells. In fact, pre-BCR expression levels measured by FACS in IL7-cultured BM pro-B/pre-B cells revealed comparable levels between wt and Fcmr deficient mice. While the survival of large pre-B cells is largely supported by pre-BCR- and IL7 receptor-mediated growth signals, both pathways are lacking in small pre-B cells. The observation that the levels of spontaneous phosphorylation of SYK and PLC2 were lower in Fcmr deficient pre-B cells as compared with normal controls suggests that expression of FCMR on small pre-B cells could sustain survival signals by promoting constitutive phosphorylation of SYK and PLCgamma2. Decreased FCMR signals could thus result in reduced clonal expansion and increased cell death, as seen in pre-B cells expressing poor quality pre-BCRs. Nonetheless, there are two issues that remain to be determined. First, the FCMR protein expression levels on the surface of pre-B cells are not known due to a lack of commercially available anti-FCMR specific Abs. Second, it is unclear if FCMR-triggered signaling requires engagement with soluble IgM. However, our analyses of Smu deficient mice that lack soluble IgM but express FCMR revealed deficiencies in pre-B cell development similar to those seen in Fcmr deficient mice, arguing that pre-B cells are very sensitive to FCMR signaling and that a certain type of interaction between sIgM and FCMR is required to generate a signaling cascade essential for development of pre-B and immature B cells. This view is further supported by the observation that sIgM enhanced production of pre-B cells in HSC reconstituted Rag1 deficient mice. Since a previous study of Smu deficient mice did not identify the defects in early B cells described in this report, the nature of FCMR-mediated signaling requires further investigation. Analyses of the effects of FCMR deficiency on subsets of mature B cells revealed two contrasting pictures with the numbers of splenic FO B cells being significantly reduced while the numbers of peritoneal B-1a cells were significantly increased. Remarkably, these observations again mirror those made in sIgM-deficient mice implicating FCMR-sIgM interactions as critical to both phenotypes. FO B cells, similar to resting small pre-B cells, are not in cell cycle and they differentiate with minimal signaling from the BCR. The lack of FCMR-augmented tonic signaling might reduce the level of FO BCR signaling below the threshold required for survival while also enhancing their apoptotic response to BCR ligation. This concept is in keeping with the known importance of tonic signaling for B cell survival demonstrated in studies of Cre-mediated ablation of BCRs in mature B cells and in mice expressing engineered BCRs without extracellular domains. It would be also consistent with the observation that Smu deficient mice, which are unable to activate the FCMR, have more apoptotic splenic B cells. The contrasting increase in peritoneal B-1a cells in FCMR-deficient mice may relate to the greater intensity of BCR signaling associated with their selection and survival than occurs with FO B cells and is associated with their anergic phenotype. As suggested by Ehrenstein and Notley from studies of sIgM-deficient mice,this strength of signaling may poise B-1a B cells at the threshold for apoptosis such that a reduction in tonic signaling would promote their survival and the observed increases in cell numbers. The known contribution of natural IgM to complement-dependent clearance of apoptotic cells provides a basis for understanding how expanded populations of B-1a cells, as a source of sIgM, could predispose mice lacking FCMR to autoimmunity. Sera from 6 month-old Fcmr deficient; mice had significantly increased levels of IgG anti-DNA antibodies and sera from nearly half of these mice were positive for ANAs with staining patterns characteristic for antibodies to dsDNA or histones. Previous studies of Smu deficient mice documented spontaneous production of IgG anti-dsDNA antibodies and glomerular deposition of IgG and C3 in about a third of 12 to 18 month old mice. Additional studies of autoimmune MRL-Fas deficient mice deficient in sIgM documented accelerated appearance of IgG anti-dsDNA and anti-histone Ab, greater renal pathology and shortened survival; IgG3 anti-dsDNA antibodies were also produced by most Smu deficient mice but only when 12 months old. Taken together, these results indicate that interactions of FCMR with natural IgM act to suppress the development of IgG secreting autoreactive B cells most likely by promoting the clearance of apoptotic cells. Previous studies of Smu deficient mice revealed impaired class switched primary immune responses to TD antigens that were explained by the lack of an adjuvant effect afforded by IgM-immunogen complexes. Interestingly, our studies of Fcmr deficient mice identified enhanced IgM responses to TD antigens, arguing for a negative rather than a positive regulatory effect on TD immune responses. Nonetheless, IgG responses to TD antigens were not similarly enhanced; indeed, IgG2b production was significantly decreased in Fcmr deficient mice. The lack of enhanced class switching in Fcmr deficient mice is associated with reduced expression of Fcmr by GC B cells and PCs. It is worth noting that the observed changes in TD immune responses by FCMR-deficient mice could be influenced by other cell types lacking FCMR and/or expression of the Fcalpha/muR that was previously shown to influence responses to different antigens. Given the abundance of natural IgM antibodies and the broad expression of FCMR, we envision that this receptor could play important roles in innate immunity. IgM immune complexes aggregated by FCMR at the cell surface are readily internalized and transported through the endocytic pathway to lysosomes where they are degraded. Engagement of this pathway to dispose of IgM-bound pathogens and extracellular debris could result in synergistic activation of B cells stimulated through their BCRs. Both our study and previous studies of Smu deficient mice demonstrated the critical roles of sIgM and FCMR in the development of innate-like B-1a and MZ B cells that are critical to responses to fungal and parasitic infections. Lack of sIgM resulted in poor responses to infection with Cryptococcus neoformans. Interestingly, natural IgM is reported to bind malarial parasites and FCMR is implicated in innate immunity against malaria infection.